Statins in patients with chronic kidney disease: why,who and when?

Importance of the field: Patients with end-stage renal disease are at high risk of developing cardiovascular disease, which is characterized by early onset and rapid progression of atherosclerosis. Some analyses of large clinical trials have revealed that statins might reduce all-cause mortality and cardiovascular (CV) events in patients with chronic kidney disease (CKD). Preliminary studies have also suggested that they can reduce contrast-induced nephropathy (CIN) and the rate of loss of kidney function. However, the results concerning the efficacy and safety of statin therapy in patients with CKD, especially in those on renal replacement therapy, are still controversial.

Areas covered in this review: This review contains data on the atherosclerotic risk in patients with CKD; the role of statins in the reduction of CV risk in patients with CKD; the role of CIN; the effects of statins on retarding the progression of CKD; and the efficacy of statin therapy in CKD, dialysis and renal-transplant patients. We searched using the electronic databases [MEDLINE (1966 – June 2010), EMBASE and SCOPUS (1965 – June 2010), DARE (1966 – June 2010)]. Additionally, abstracts from national and international cardiovascular meetings were studied. Where necessary, the relevant authors of these studies were contacted to obtain further data. The main data search terms were: ‘statin/statins’, ‘dialysis’, ‘dyslipidemia’, ‘hemodialysis’, ‘kidney disease’, ‘microalbuminuria’, ‘clinical trials’, and ‘renal impairment’.

What the reader will gain: Readers will be acquainted with results of clinical trials, including the most recent ones (e.g., PLANETE I and II), and will be able to draw their own conclusions concerning the use of statins in CKD patients on the basis of the results of the studies presented and to compare them with the authors' suggestions presented in this review.

Take home message: Although the results of trials are conflicting, it is suggested that the benefits of statin use outweigh the drawbacks in patients with early-stage CKD, when the benefits can be effectively predicted. However, available large randomized clinical trials suggest a lack of efficacy in patients on renal replacement therapy.     

Lipid-lowering agents for concurrent cardiovascular and chronic kidney disease

ABSTRACT

Introduction: Cardiovascular disease (CVD) frequently co-exists with chronic kidney disease (CKD). Patients with concomitant CVD and CKD are at very high risk of CVD events.

Areas covered: This narrative review discusses the use of hypolipidaemic drugs in patients with both CVD and CKD. Current guidelines are considered together with the evidence from randomised controlled clinical trials.

Expert opinion: Statins are the first-line lipid-lowering therapy in patients with CVD and CKD. Some statins require dose adjustments based on renal function, whereas atorvastatin does not. Ezetimibe can be prescribed in patients with CVD and CKD, usually combined with a statin. According to current guidelines, statin±ezetimibe therapy should not be initiated, but should be continued, in dialysis-treated CKD patients. Fenofibrate (dose adjusted or contra-indicated according to renal function) and omega 3 fatty acids lower triglyceride levels; whether they also exert cardiorenal benefits in patients with CVD and CKD remains to be established. The use of proprotein convertase subtilisin-kexin type 9 (PCSK9) inhibitors, cholesterol-reducing nutraceuticals, bempedoic acid and apabetalone in such patients should be investigated. Patients with concomitant CVD and CKD should be treated, in terms of lipid-lowering therapy, early and intensively to minimize their very high risk and possibly, progression of CKD.     

The safety and effectiveness of statins as treatment for HIV-dyslipidemia: the evidence so far and the future challenges

Introduction: Statin therapy is widely used across the globe for the treatment and prevention of cardiovascular disease (CVD). It is well established that statin therapy is associated with significant decrease in low-density lipoprotein cholesterol (LDL-C) and plasma cholesterol levels. HIV-dyslipidemia is a common problem with extensive use of combination antiretroviral therapy (CART), and is associated with an increase in incidence of cardiovascular disease (CVD), resulting in hospital admission and surgery throughout the western healthcare systems.

Areas covered: This review describes the effectiveness and safety of statins in the treatment of HIV-dyslipidemia. Medline was searched for different statins as treatment for HIV-dyslipidemia.

Expert opinion: Dyslipidemia in patients with HIV is different from the normal population, due to the fact that HIV treatment may not only cause dyslipidemia, but may also interact with lipid lowering medication. Statin-unresponsive HIV-dyslipidemia can be treated with the addition of ezetimibe, fenofibrate, fish oil and niacin. Current guidelines recommend the use of pravastatin and atorvastatin as first-line therapy, whereas European guidelines include rosuvastatin. There is an urgent need to confirm whether the use of statins in HIV-dyslipidemia is associated with an increase in the incidence of diabetes; this is significant because HIV patients are known to be insulin-resistant. HIV is also associated with Non-alcoholic Fatty Liver Disease (NAFLD), a condition known to be associated with insulin resistance. Further clinical trials are urgently needed to assess the impact of statins on CVD in HIV patients, and future challenges for researchers in this area are enormous.     

Statin discontinuation in high-risk patients: a systematic review of the evidence

Hypercholesterolemia is a major risk factor for cardiovascular disease (CVD), the leading cause of death worldwide. Since the late 1980s, statins have emerged as effective lipid-lowering therapies and are now widely used to protect against and slow the progression of CVD and cerebrovascular disease. However, there is a significant gap between disease improvement in clinical trials and daily practice possibly attributable to poor adherence with statin therapy. High discontinuation rates were reported in primary and secondary prevention. This systematic review aims to summarize the current literature regarding the association between statin therapy discontinuation and cardiovascular and cerebrovascular events and all-cause mortality in high-risk patients. Available English literature was reviewed using Medline, Embase, Web of Sciences and the Cochrane Library; 39 studies were identified. In primary and secondary prevention, as well as perioperatively, non-adherence or discontinuation of statin therapy was associated with detrimental effects on cardiovascular and cerebrovascular outcomes, including disease severity and mortality. Importantly, some studies reported that very low adherence and discontinuation was associated with worse outcomes than never using statins. In conclusion, non-adherence and discontinuation of statin therapy significantly increased the incidence of cardiovascular and cerebrovascular events as well as all-cause mortality in high-risk patients. Patients would therefore benefit from closer adherence assessment and education programs aimed at increasing awareness of the risk associated with discontinuation of statin therapy.     

Statins can improve proteinuria and glomerular filtration rate loss in chronic kidney disease patients,further reducing cardiovascular risk. Fact or fiction?

Introduction: The prevalence of chronic kidney disease (CKD), a risk factor for cardiovascular disease (CVD), is increasing worldwide. Statin treatment, the cornerstone of prevention or treatment of CVD, might have beneficial effects on urine protein excretion and renal function as determined by the glomerular filtration rate, whereas it might protect from acute kidney injury (AKI), mainly due to contrast-induced AKI. These beneficial effects on CKD may not be drug class effects; specific statins at specific doses may help prevent CKD deterioration and reduce CVD risk. We analysed all statin studies that had renal and CVD endpoints as main outcome measures. MEDLINE, EMBASE and the Cochrane Central Register of Controlled Trials were searched up to February 2015.

Areas covered: We consider the effects of statins on microalbuminuria, proteinuria, glomerular filtration rate, AKI associated with angiography or percutaneous coronary intervention and on CVD event rates in patients with CKD.

Expert opinion: Current evidence points towards the need to prescribe high-potency statins in patients with CKD, before a major decline in kidney function occurs. This may reduce CVD risk and delay the progress of CKD. Administration of either atorvastatin or rosuvastatin can prevent contrast-induced AKI before angiography or percutaneous coronary intervention. The combination of simvastatin + ezetimibe may decrease vascular events in patients with advanced CKD.     

Fenofibrate plus simvastatin (fixed-dose combination) for the treatment of dyslipidaemia

Introduction: Statin use results in a significant reduction of cardiovascular disease (CVD) risk. However, patients still have residual CVD risk, even if they are receiving optimal statin treatment.

Areas covered: This review, based on a Pubmed/Scopus search, discusses the available evidence regarding the use of a fixed-dose fenofibrate plus simvastatin combination. This combination is useful for patients with mixed dyslipidaemia because it improves the overall lipoprotein profile. Although in clinical trials the rate of adverse events was not significantly greater than monotherapy, patients who receive combination treatment should be monitored carefully. Furthermore, in the Action to Control Cardiovascular Risk in Diabetes (ACCORD) Study, this combination did not result in a significant reduction of CVD events compared with simvastatin monotherapy. However, a possible benefit in this trial was observed in the subgroup of patients with high triglyceride and low high-density lipoprotein cholesterol levels.

Expert opinion: The fixed-dose fenofibrate plus simvastatin combination treatment produces additive results and is safe when patients are properly monitored. Existing evidence appears to support the addition of fenofibrate to simvastatin treatment for the reduction of residual CVD risk in patients with atherogenic dyslipidaemia. However, this combination did not lead to better clinical outcomes in the absence of dyslipidaemia.     

Nephroprotective and clinical potential of statins in dialyzed patients

Background: The combination of increased cardiovascular mortality and vascular complications due to dyslipidaemia in chronic kidney disease (CKD) has focused attention onto the potential beneficial effects of 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMG-CoA) inhibitors (statins) on the course of CKD. Objective: To examine the use of statins in CKD. Methods: A review of relevant literature. Results/conclusion: Current evidence from clinical trials in CKD patients on maintenance dialysis is limited. Therefore, the routine use of statins in this population remains the decision of individual physicians in discussion with their patients.     

LDL-C reductions and goal attainment among naive statin users in the Netherlands: real life results*

ABSTRACT

Objective: The effectiveness of statin therapy in a real life setting may differ from that in clinical trials, as physicians make non-randomised treatment decisions for patients with less uniform and possibly different characteristics. We therefore performed a study to compare the effectiveness of different statins and doses in routine clinical practice with respect to total serum cholesterol and LDL-cholesterol (LDL-C) reduction and goal attainment according to European guidelines on the prevention of cardiovascular disease (CVD).

Research design and methods: Naive statin users starting treatment in 2003 and 2004 with LDL-C measurements at baseline and between 30 and 365 days after start of treatment were extracted from the PHARMO database. During treatment with their initial statin dose LDL-C reduction and attainment of cholesterol goals were compared between different statins and doses.

Results: Of 2303 identified naive patients, approximately 30% were allocated to the high CVD-risk group. Average LDL-C reductions were 48%, 42%, 39%, and 32% at mean doses of 11 mg rosuvastatin, 17 mg atorvastatin, 22 mg simvastatin and 35 mg pravastatin, respectively. The proportion of patients attaining cholesterol goals was 75% for rosuvastatin, 68% for atorvastatin, 56% for simvastatin, and 42% for pravastatin. Dose comparisons showed greater LDL-C reduction and increased goal attainment for rosuvastatin 10 mg compared to other statins at most doses (adjusted p < 0.05).

Conclusions: In a real life setting, both LDL-C reduction and the proportion of patients attaining cholesterol goals appear to be significantly increased among users of rosuvastatin compared to other statins. These results confirm and extend reported clinical trial results to a real world setting.     

Family history of cardiovascular disease and influence on statin therapy persistence

Purpose

Persistence to statins is low, presumably due to lack of perception of risk. Having a close relative suffering from cardiovascular disease (CVD) might increase persistence to statins. We investigated whether family history of CVD influences the discontinuation of statin treatment.

Methods

A population-based cohort study was performed. Swedish registers on dispensed drugs, hospitalization and cause of death were linked to the Multi-generation Register. Incident statin users 20–72 years of age were identified between 2006 and 2007 and followed until 30 June 2009. Family history of CVD was defined as the presence of relatives with a previous cardiovascular event. Cox regression was used to study discontinuation and estimate the effect of the family history of CVD, adjusting for gender, age, education, income, healthcare provider, prevention’s type, birth’s country and residence’s county. Stratified analysis by type and severity of cardiovascular event was performed.

Results

A total of 86,002 patients were enrolled; 61.5 % had a family history of CVD. Discontinuation of statin therapy was not associated with family history of CVD (HR: 0.98; 95 % CI:0.96–1.01), except for patients with a family history of death from myocardial infarction (MI) (HR: 0.95 95 % CI:0.92–0.98). Young age, foreign background, low income, and statin for primary prevention and for secondary prevention when prescribed by a general practitioner were associated with higher risk of statin discontinuation.

Conclusions

Having relatives suffering from CVD did not consistently influence the persistence to statin treatment. A family history of death from MI had a slight significant positive effect on statin persistence, though not clinically relevant.     

Effects on Coronary Atherosclerosis by Targeting Low-Density Lipoprotein Cholesterol with Statins

A correlation exists between circulating levels of low-density lipoprotein cholesterol (LDL-C) and risk of cardiovascular disease (CVD). Evidence from clinical trials indicates that reducing LDL-C levels can result in beneficial clinical outcomes in patients at risk of CVD and in high-risk patients with clinical symptoms of CVD. Lipid-lowering agents, of which HMG-CoA reductase inhibitors (statins) are the most effective, protect against the vascular changes seen in the development of atherosclerotic plaque formation. Clinical trials assessing the effects of statins on coronary atherosclerosis using quantitative coronary angiography or intravascular ultrasound showed that statins can reduce progression or even cause regression of atherosclerotic plaque. This improvement of vascular structure after statin treatment is correlated with reductions in LDL-C levels. This appears to be the principal mechanism by which statin therapy reduces cardiovascular risk, with emerging evidence for statin-mediated changes in high-density lipoprotein and C-reactive protein levels contributing to modification of the atherosclerotic plaque.     

Statin myopathy: the fly in the ointment for the prevention of cardiovascular disease in the 21st century?

Introduction: Cardiovascular disease (CVD) remains the leading cause of death in industrialized nations. Despite clear evidence of CVD risk reduction with HMG-CoA reductase inhibitors (statins), the side effects of these medications, particularly myopathy, limit their effectiveness. Studies into the mechanisms, aetiology and management of statin myopathy are limited by lack of an internationally agreed clinical definition and tools for assessing outcomes. Currently there is a paucity of evidence to guide the management of patients affected by statin myopathy; with the exception of dose reduction, there is little evidence that other strategies can improve statin tolerance, and even less evidence to suggest these alternate dosing strategies reduce cardiovascular risk.

Areas covered: This review will cover current definitions, clinical presentations, risk factors, pathogenesis and management. PubMed was searched (English language, to 2014) for key articles pertaining to statin myopathy. This review then briefly describes our experience of managing this condition in a tertiary lipid disorders clinic, in the setting of limited guiding evidence.

Expert opinion: Knowledge gaps in the field of statin myopathy are identified and future research directions are suggested. We urge the need for international attention to address this important, but largely neglected clinical problem, that if unresolved will remain an impediment to the effective prevention and treatment of CVD.     

Statins and the potential for higher diabetes mellitus risk

ABSTRACT

Introduction: 3-Hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors (statins) are widely used for cardiovascular disease (CVD) prevention. Long-term use of statins has been linked to the development of diabetes mellitus (DM) which increases CVD risk.

Areas covered: We discussed the reported incidence of DM in statin users, various possible mechanisms responsible for the development of DM and the clinical implications of this association on CVD risk. Relevant supporting literature was identified using MEDLINE/EMBASE search.

Expert opinion: Data from available RCTs and observational studies suggest a 10–45% higher risk of new-onset DM with statin use compared to nonusers. Several cellular, molecular, and genetic mechanisms, and lifestyle changes have been studied and discussed as potential underlying mechanisms responsible for this elevated DM risk with statin therapy. The mode of the diabetogenic action of statins is still unclear and an interplay of pancreatic and peripheral effects in the pathogenesis of DM is a possibility. Despite these observations, the CVD preventative benefit of statin treatment outweighs the CVD risk associated with of development of new DM. There is a need for further research to identify the exact mechanisms involved so as to specifically target causative factors and individualize treatment.     

Pharmacological strategies to reduce cardiovascular risk in type 2 diabetes mellitus: an update

Morbidity and mortality in patients with type 2 diabetes mellitus is largely dominated by the occurrence of cardiovascular disease (CVD). Treatment of known risk factors of CVD has proven to be beneficial in terms of reduction in risk of major CVD events in the general population. Recent trials have provided information on the treatment of hyperglycaemia, hypertension, dyslipidaemia and platelet aggregation in the patient with type 2 diabetes.Strict glycaemic control is not associated with a significant reduction in CVD risk, although new hypoglycaemic agents may offer additional benefits. In contrast, it has been demonstrated that treatment of hypertension and dyslipidaemia significantly reduce cardiovascular risk. Meticulous control of blood pressure to a level < or =130/80 mm Hg, preferably using renin-angiotensin system-modulating agents, is of proven value. Use of HMG-CoA reductase inhibitors (statins) as low-density lipoprotein (LDL)-cholesterol-lowering therapy, initiated at a level of > or =2.60 mmol/L is firmly established. Recent trials lend support to lowering the target level for LDL-cholesterol-lowering therapy to < or =1.81 mmol/L. Mainly based on risk analogy, international guidelines advocate the use of aspirin (acetylsalicylic acid) in the primary prevention of CVD in patients with type 2 diabetes. However, there is no support from large trials that the estimated 25% risk reduction in primary prevention in a high-risk population is the same in the subgroup with diabetes.An intensified approach in order to identify and treat cardiovascular risk factors in patients with type 2 diabetes, stratified to individual patients, is necessary to reduce the excess cardiovascular burden of these patients.     

Cumulative clinical trial data on atorvastatin for reducing cardiovascular events: the clinical impact of atorvastatin

ABSTRACT

Background: Since the 1990s a multitude of statin trials have definitively demonstrated the ability of statin therapy to reduce the risk of adverse coronary heart disease (CHD) events. Among these, the Atorvastatin Landmarks program – a group of 32 major atorvastatin trials – has assessed the efficacy and safety of atorvastatin across its full dose range and has helped illustrate its effectiveness in treatment of cardiovascular disease and its related disorders and also in non-cardiovascular outcomes.

Scope: This paper will review the major atorvastatin clinical trials and report the important findings and their clinical significance.

Findings: Clinical trials with atorvastatin have established significant reductions in cardiovascular events in patients with and without CHD. Studies show that high-dose atorvastatin will reduce LDL to ≈?70?mg/dL in many patients and improve cardiac outcomes. Current evidence suggests that high-dose atorvastatin can halt and, in some cases, reverse atherosclerotic progression. A study of diabetic patients showed atorvastatin decreased the occurrence of acute CHD events, coronary revascularizations, and stroke. Atorvastatin has been found to be effective for reducing nonfatal myocardial infarctions and fatal CHD in hypertensive patients with three or more additional risk factors. High-dose atorvastatin was found to be effective in reducing risk of recurrent stroke in patients with prior cerebrovascular events, has been shown to benefit patients suffering a recent acute coronary syndrome, and to slow cognitive decline in preliminary studies of patients with Alzheimer's disease. Atorvastatin has been associated with reduced progression of mild chronic kidney disease; however, in a randomized trial of patients with end stage renal disease on hemodialysis, atorvastatin showed no statistically significant benefit. Limitations of this review include lack of generalizablity of the atorvastatin trial data to other statins, lack of head to head outcome trials involving the newer more potent statins, and the relatively short study durations (none exceeded 5 years) when atherosclerosis is typically a decades-long disease.

Conclusion: A compelling body of evidence documents that atorvastatin reduces major cardiovascular events in both secondary and primary prevention of CHD and in a broad range of patients and disease conditions. Furthermore, throughout its dose range, atorvastatin is safe and well tolerated.     

Impact of gender on statin efficacy

ABSTRACT

Objective: To determine the impact of statin therapy on the combined endpoint of cardiovascular events in women and men separately.

Research design and methods: A systematic literature search through May 2006 was conducted to identify randomized, controlled statin trials evaluating the gender specific incidence of cardiovascular events. Weighted averages were reported as relative risks (RRs) with 95% confidence intervals (CI) calculated via random-effects model.

Main outcome measures: The primary outcome measured was a composite endpoint of all cardiovascular events. Secondary outcomes measured included death, myocardial infarction (MI), and stroke.

Results: Fifteen trials were included in this meta-analysis. Cardiovascular events were reduced in men (RR 0.76 [95% CI 0.70, 0.81]) and women (RR 0.79 [95% CI 0.69, 0.90]). Reductions in mortality, MI, and stroke predominantly contributed to the reduction in cardiovascular events in men taking statins. Women did not have a reduction in mortality or stroke, suggesting that the reductions in cardiac events may have been predominantly due to reductions in need for revascularization and/or unstable angina.

Conclusions: Statins reduced the risk of cardiovascular events in men and women, but women on statins may not have reductions in mortality and stroke like their male counterparts.     

Statins as potential treatment for cholesterol gallstones: an attempt to understand the underlying mechanism of actions

Introduction: Statin therapy is widely used across the globe for the treatment and prevention of cardiovascular disease (CVD). It is well established that statin therapy is associated with significant decreases in low-density lipoprotein cholesterol (LDL-C) and plasma cholesterol levels. Cholesterol gallstones are a common problem, resulting in hospital admission and surgery, throughout western healthcare systems.

Areas covered: This review describes the mechanisms, and addresses the potential, for statins to be used as a treatment for gallstones. Medline was searched for the risk factors and treatment of cholesterol gallstones.

Expert opinion: Obesity, metabolic syndrome, non-alcoholic fatty liver disease (NAFLD), insulin resistance and high-fat diets (unsaturated fats) rich in cholesterol are all associated risk factors for cholesterol gallstones. In view of the high prevalence of cholesterol gallstones, there is an urgent need to understand whether pharmacological therapies can be harnessed for the treatment of cholesterol gallstones. Gallstones are shown to be associated with an increased risk, not only of mortality, but also of CVD. Statins, widely used in prevention of CVD and hypercholesteremia, have been shown to dissolve cholesterol gallstones in animal models and human studies, highlighting the potential for a pharmacological therapy for gallstones. More studies are required to understand the role of statins in the treatment of gallstones and for comparison with current treatment strategies.     

Statins and muscle pain

ABSTRACT

Introduction: Statins remain among the most frequently prescribed drugs and constitute a cornerstone in the prevention of cardiovascular disease. However, muscle symptoms are often reported from patients on statins. Muscle symptoms are frequently reported as adverse events associated with statin therapy.

Areas covered: In the present narrative review, statin-associated muscle pain is discussed. It elucidates potential mechanisms and possible targets for management.

Expert opinion: In general, the evidence in support of muscle pain caused by statins is in some cases equivocal and not particularly strong. Reported symptoms are difficult to quantify. Rarely is it possible to establish a causal link between statins and muscle pain. In randomized controlled trials, statins are well tolerated, and muscle-pain related side-effects is similar to placebo. There are also nocebo effects of statins. Exchange of statin may be beneficial although all statins have been associated with muscle pain. In some patients reduction of dose is worth trying, especially in primary prevention Although the benefits of statins outweigh potential risks in the vast majority of cases, careful clinical judgment may be necessary in certain cases to manage potential side effects on an individual basis.     

Statin drug interactions and related adverse reactions

Introduction: Statin monotherapy is generally well tolerated, with a low frequency of adverse events. The most important adverse effects associated with statins are myopathy and an asymptomatic increase in hepatic transaminases, both of which occur infrequently. Because statins are prescribed on a long-term basis, their possible interactions with other drugs deserve particular attention, as many patients will typically receive pharmacological therapy for concomitant conditions during the course of statin treatment.

Areas covered: This review summarizes the pharmacokinetic properties of statins and emphasizes their clinically relevant drug interactions and related adverse reactions.

Expert opinion: Avoiding drug–drug interactions and consequent adverse drug reactions is essential in order to optimize compliance, and thus improve the treatment of patients at high cardiovascular risk. The different pharmacokinetic profiles among statins should be carefully considered, in order to understand the possible spectrum of drug interactions. The growing trend toward earlier statin treatment for the prevention of cardiovascular disease means that physicians must anticipate future polypharmacy when their patients require additional medications for comorbid conditions.     

Is there a future for direct renin inhibitors?

Importance of the field: The renin-angiotensin-aldosterone system (RAAS) is a key regulator of blood pressure (BP), as well as volume and electrolytes, in both hypertensive and normotensive individuals. Inappropriate activation of the RAAS is important in hypertension-induced cardiovascular disease (CVD) and chronic kidney disease (CKD). Renin is the rate-limiting step in the RAAS cascade, which makes direct renin inhibitors (DRIs) an attractive target for RAAS suppression and treatment of hypertension. Current regimens using either angiotensin-converting enzyme inhibitor (ACEi) or angiotensin receptor blocker (ARB) result in feedback upregulation of renin and aldosterone breakthrough, which contribute to incomplete suppression of the RAAS. Thereby, aliskiren – alone or in combination – might offer a novel therapeutic intervention to improve suppression of the RAAS, with potential to translate to improved CVD and CKD outcomes.

Areas covered in this review: Herein, we present the current state of knowledge of DRIs in the preclinical and clinical realm and their antihypertensive efficacy in relation to cardiovascular and renal risk. Recent clinical trials (2007 – 2009) support the efficacy of aliskiren, and studies suggest the potential for improved CVD and CKD outcomes.

What the reader will gain: An understanding of the mechanism of action of DRIs and a perspective of recent clinical trials.

Take home message: The DRI aliskiren is an effective antihypertensive agent that preliminary data suggests has a beneficial effect in CVD and CKD. Combination of aliskiren with an ACEi or ARB may be better tolerated than the ACEi–ARB combination. Future work is needed to further quantify aliskiren's impact on hard CVD and CKD end points.